Two important problems affect the ability of asexual populations to accumulate beneficial mutations, and hence to adapt. First, clonal interference causes some beneficial mutations to be outcompeted by more-fit mutations which occur in the same genetic background. Second, multiple mutations occur in some individuals, so even mutations of large effect can be outcompeted unless they occur in a good genetic background which contains other beneficial mutations. In this paper, we use a Monte Carlo simulation to study how these two factors influence the adaptation of asexual populations. We find that the results depend qualitatively on the shape of the distribution of the effects of possible beneficial mutations. When this distribution falls off slower than exponentially, clonal interference alone reasonably describes which mutations dominate the adaptation, although it gives a misleading picture of the evolutionary dynamics. When the distribution falls off faster than exponentially, an analysis based on multiple mutations is more appropriate. Using our simulations, we are able to explore the limits of validity of both of these approaches, and we explore the complex dynamics in the regimes where neither are fully applicable.
Linked beneficial and deleterious mutations are known to decrease the fixation probability of a favorable mutation in large asexual populations. While the hindering effect of strongly deleterious mutations on adaptive evolution has been well studied, how weak deleterious mutations, either in isolation or with superior beneficial mutations, influence the fixation of a beneficial mutation has not been fully explored. Here, using a multitype branching process, we obtain an accurate analytical expression for the fixation probability when deleterious effects are weak, and exploit this result along …
In an adapted population of mutators in which most mutations are deleterious, a nonmutator that lowers the mutation rate is under indirect selection and can sweep to fixation. Using a multitype branching process, we calculate the fixation probability of a rare nonmutator in a large population of asexual mutators. We show that when beneficial mutations are absent, the fixation probability is a nonmonotonic function of the mutation rate of the mutator: it first increases sublinearly and then decreases exponentially. We also find that beneficial mutations can enhance the fixation probability of a…
We study a continuous time model for the frequency distribution of an infinitely large asexual population in which both beneficial and deleterious mutations occur and the fitness is additive. When beneficial mutations are ignored, the exact solution for the frequency distribution is known to be a Poisson distribution. Here we include beneficial mutations and obtain exact expressions for the frequency distribution at all times using an eigenfunction expansion method. We find that the stationary distribution is non-Poissonian and related to the Bessel function of the first kind. We also provide …
The rate of recombination affects the mode of molecular evolution. In high-recombining sequence, the targets of selection are individual genetic loci; under low recombination, selection collectively acts on large, genetically linked genomic segments. Selection under linkage can induce clonal interference, a specific mode of evolution by competition of genetic clades within a population. This mode is well known in asexually evolving microbes, but has not been traced systematically in an obligate sexual organism. Here we show that the Drosophila genome is partitioned into two modes of evolution:…
In large asexual populations, beneficial mutations have to compete with each other for fixation. Here, I derive explicit analytic expressions for the rate of substitution and the mean beneficial effect of fixed mutations, under the assumptions that the population size N is large, that the mean effect of new beneficial mutations is smaller than the mean effect of new deleterious mutations, and that new beneficial mutations are exponentially distributed. As N increases, the rate of substitution approaches a constant, which is equal to the mean effect of new beneficial mutations. The mean effect …
Genome sizes have evolved to vary widely, from 250 bases in viroids to 670 billion bases in amoeba. This remarkable variation in genome size is the outcome of complex interactions between various evolutionary factors such as point mutation rate, population size, insertions and deletions, and genome editing mechanisms that may be specific to certain taxonomic lineages. While comparative genomics analyses have uncovered some of the relationships between these diverse evolutionary factors, we still do not understand what drives genome size evolution. Specifically, it is not clear how primordial m…
The adaptation of large asexual populations is hampered by the competition between independently arising beneficial mutations in different individuals, which is known as clonal interference. Fisher and Muller proposed that recombination provides an evolutionary advantage in large populations by alleviating this competition. Based on recent progress in quantifying the speed of adaptation in asexual populations undergoing clonal interference, we present a detailed analysis of the Fisher-Muller mechanism for a model genome consisting of two loci with an infinite number of beneficial alleles each …
The mutation rate of a well adapted population is prone to reduction so as to have a lower mutational load. We aim to understand the role of epistatic interactions between the fitness affecting mutations in this process. Using a multitype branching process, the fixation probability of a single non-mutator emerging in a large asexual mutator population is analytically calculated here. The mutator population undergoes deleterious mutations at constant, but at a much higher rate than that of the non-mutator. We find that antagonistic epistasis lowers the chances of mutation rate reduction, while …
Seagrass meadows are among the most important coastal ecosystems, in terms of both spatial extent and ecosystem services, but they are also declining worldwide. Understanding the drivers of seagrass meadow dynamics is essential for designing sound management, conservation, and restoration strategies. However, the poor knowledge of the effect of clonality on the population genetics of natural populations severely limits our understanding of the dynamics and connectivity of meadows. Recent modelling approaches have described the expected distributions of genotypic and genetic descriptors under i…
Many species reproduce both sexually and asexually producing genetically unique and clonal recruits. The relative contribution of sexual and asexual reproduction is mostly considered a consequence of natural selection, for example, disfavouring sexual propagules during invasions. Here, we present a novel model for the invasion of species into a new habitat. The model is fully neutral with respect to the dispersal and the survival of sexual and asexual recruits. In addition to local dispersal through sexual and asexual reproduction, long-distance dispersal is implemented through a non-zero prob…
A mutator is an allele that increases the mutation rate throughout the genome by disrupting some aspect of DNA replication or repair. Mutators that increase the mutation rate by the order of 100 fold have been observed to spontaneously emerge and achieve high frequencies in natural populations and in long-term laboratory evolution experiments with \textit{E. coli}. In principle, the fixation of mutator alleles is limited by (i) competition with mutations in wild-type backgrounds, (ii) additional deleterious mutational load, and (iii) random genetic drift. Using a multiple locus model and emplo…
Although mutations drive the evolutionary process, the rates at which the mutations occur are themselves subject to evolutionary forces. Our purpose here is to understand the role of selection and random genetic drift in the evolution of mutation rates, and we address this question in asexual populations at mutation-selection equilibrium neglecting selective sweeps. Using a multitype branching process, we calculate the fixation probability of a rare nonmutator in a large asexual population of mutators, and find that a nonmutator is more likely to fix when the deleterious mutation rate of the m…
Sex in higher diploids carries a two-fold cost of males that should reduce its fitness relative to cloning and result in its extinction. Instead, sex is widespread and it is clonal species that face early obsolescence. One possible reason is that sex is an adaptation to resist ubiquitous parasites, which evolve rapidly and potentially antagonistically. We use a heuristic approach to model mutation-selection in finite populations where a parasitic haploid mounts a negative frequency-dependent attack on a diploid host. The host evolves reflexively to reduce parasitic load. Both host and parasite…
In large asexual populations, multiple beneficial mutations arise in the population, compete, interfere with each other, and accumulate on the same genome, before any of them fix. The resulting dynamics, although studied by many authors, is still not fully understood, fundamentally because the effects of fluctuations due to the small numbers of the fittest individuals are large even in enormous populations. In this paper, branching processes and various asymptotic methods for analyzing the stochastic dynamics are further developed and used to obtain information on fluctuations, time dependence…
How self-incompatibility systems are maintained in plant populations is still a debated issue. Theoretical models predict that self-incompatibility systems break down according to the intensity of inbreeding depression and number of S-alleles. Other studies have explored the function of asexual reproduction in the maintenance of self-incompatibility. However, the population genetics of partially asexual, self-incompatible populations are poorly understood and previous studies have failed to consider all possible effects of asexual reproduction or could only speculate on those effects. In this …
We consider a model of asexually reproducing individuals with random mutations and selection. The rate of mutations is proportional to the population size, $N$. The mutations may be either beneficial or deleterious. In a paper by Yu, Etheridge and Cuthbertson (2009) it was conjectured that the average rate at which the mean fitness increases in this model is $O(\log N/(\log\log N)^2)$. In this paper we show that for any time $t > 0$ there exist values $ε_N \rightarrow 0$ and a fixed $c > 0$ such that the maximum fitness of the population is greater than $cs\log N/(\log\log N)^2$ for all times …
The accumulation of adaptive mutations is essential for survival in novel environments. However, in clonal populations with a high mutational supply, the power of natural selection is expected to be limited. This is due to clonal interference - the competition of clones carrying different beneficial mutations - which leads to the loss of many small effect mutations and fixation of large effect ones. If interference is abundant, then mechanisms for horizontal transfer of genes, which allow the immediate combination of beneficial alleles in a single background, are expected to evolve. However, t…
We show that the Eigen model and the asexual Wright-Fisher model can be obtained as different limit cases of a unique stochastic model. This derivation makes clear which are the exact differences between these two models. The two key concepts introduced with the Eigen model, the error threshold and the quasispecies, are not affected by these differences, so that they are naturally present also in population genetics models. According to this fact, in the last part of the paper, we use the classical diploid mutation-selection equation and the single peak fitness approximation to obtain the erro…
RNA virus populations will undergo processes of mutation and selection resulting in a mixed population of viral particles. High throughput sequencing of a viral population subsequently contains a mixed signal of the underlying clones. We would like to identify the underlying evolutionary structures. We utilize two sources of information to attempt this; within segment linkage information, and mutation prevalence. We demonstrate that clone haplotypes, their prevalence, and maximum parsimony reticulate evolutionary structures can be identified, although the solutions may not be unique, even for …
Character evolution that affects ecological community interactions often occurs contemporaneously with temporal changes in population size, potentially altering the very nature of those dynamics. Such eco-evolutionary processes may be most readily explored in systems with short generations and simple genetics. Asexual and cyclically parthenogenetic organisms such as microalgae, cladocerans, and rotifers, which frequently dominate freshwater plankton communities, meet these requirements. Multiple clonal lines can coexist within each species over extended periods, until either fixation occurs or…
On rugged fitness landscapes where sign epistasis is common, adaptation can often involve either individually beneficial "uphill" mutations or more complex mutational trajectories involving fitness valleys or plateaus. The dynamics of the evolutionary process determine the probability that evolution will take any specific path among a variety of competing possible trajectories. Understanding this evolutionary choice is essential if we are to understand the outcomes and predictability of adaptation on rugged landscapes. We present a simple model to analyze the probability that evolution will es…
We study the competition between several advantageous mutants in an asexual population (clonal interference) as a function of the time between the appearance of the mutants, their selective advantages, and the rate of deleterious mutations. We find that the overall probability of fixation (the probability that at least one of the mutants becomes the ancestor of the entire population) does not depend on the time interval between the appearance of these mutants, and equals the probability that a genotype bearing all of these mutations reaches fixation. This result holds also in the presence of d…
We use traveling-wave theory to derive expressions for the rate of accumulation of deleterious mutations under Muller's ratchet and the speed of adaptation under positive selection in asexual populations. Traveling-wave theory is a semi-deterministic description of an evolving population, where the bulk of the population is modeled using deterministic equations, but the class of the highest-fitness genotypes, whose evolution over time determines loss or gain of fitness in the population, is given proper stochastic treatment. We derive improved methods to model the highest-fitness class (the st…
In large populations, multiple beneficial mutations may be simultaneously spreading. In asexual populations, these mutations must either arise on the same background or compete against each other. In sexual populations, recombination can bring together beneficial alleles from different backgrounds, but tightly linked alleles may still greatly interfere with each other. We show for well-mixed populations that when this interference is strong, the genome can be seen as consisting of many effectively asexual stretches linked together. The rate at which beneficial alleles fix is thus roughly propo…
Using a lattice model based on Monte Carlo simulations, we study the role of the reproduction pattern on the fate of an evolving population. Each individual is under the selection pressure from the environment and random mutations. The habitat ("climate") is changing periodically. Evolutions of populations following two reproduction patterns are compared, asexual and sexual. We show, via Monte Carlo simulations, that sexual reproduction by keeping more diversified populations gives them better chances to adapt themselves to the changing environment. However, in order to obtain a greater chance…
We study the evolutionary dynamics of an asexual population of nonmutators and mutators on a class of epistatic fitness landscapes. We consider the situation in which all mutations are deleterious and mutators are produced from nonmutators continually at a constant rate. We find that in an infinitely large population, a minimum nonmutator-to-mutator conversion rate is required to fix the mutators but an arbitrarily small conversion rate results in the fixation of mutators in a finite population. We calculate analytical expressions for the mutator fraction at mutation-selection balance and fixa…
The importance of mutator clones in the adaptive evolution of asexual populations is not fully understood. Here we address this problem by using an ab initio microscopic model of living cells, whose fitness is derived directly from their genomes using a biophysically realistic model of protein folding and interactions in the cytoplasm. The model organisms contain replication controlling genes (DCGs) and genes modeling the mismatch repair (MMR) complexes. We find that adaptation occurs through the transient fixation of a mutator phenotype, regardless of particular perturbations in the fitness l…
The adaptive evolution of large asexual populations is generally characterized by competition between clones carrying different beneficial mutations. This interference phenomenon slows down the adaptation speed and makes the theoretical description of the dynamics more complex with respect to the successional occurrence and fixation of beneficial mutations typical of small populations. A simplified modeling framework considering multiple beneficial mutations with equal and constant fitness advantage captures some of the essential features of the actual complex dynamics, and some key prediction…
The vast majority of mutations are deleterious, and are eliminated by purifying selection. Yet in finite asexual populations, purifying selection cannot completely prevent the accumulation of deleterious mutations due to Muller's ratchet: once lost by stochastic drift, the most-fit class of genotypes is lost forever. If deleterious mutations are weakly selected, Muller's ratchet turns into a mutational "meltdown" leading to a rapid degradation of population fitness. Evidently, the long term stability of an asexual population requires an influx of beneficial mutations that continuously compensa…
We consider an exponentially growing population of cells undergoing mutations and ask about the effect of reproductive fluctuations (genetic drift) on its long-term evolution. We combine first step analysis with the stochastic dynamics of a birth-death process to analytically calculate the probability that the parent of a given genotype will go extinct. We compare the results with numerical simulations and show how this turnover of genetic clones can be used to infer the rates underlying the population dynamics. Our work is motivated by growing populations of tumour cells, the epidemic spread …
When beneficial mutations are rare, they accumulate by a series of selective sweeps. But when they are common, many beneficial mutations will occur before any can fix, so there will be many different mutant lineages in the population concurrently. In an asexual population, these different mutant lineages interfere and not all can fix simultaneously. In addition, further beneficial mutations can accumulate in mutant lineages while these are still a minority of the population. In this paper, we analyze the dynamics of such multiple mutations and the interplay between multiple mutations and inter…
In large clonal populations, several clones generally compete which results in complex evolutionary and ecological dynamics: experiments show successive selective sweeps of favorable mutations as well as long-term coexistence of multiple clonal strains. The mechanisms underlying either coexistence or fixation of several competing strains have rarely been studied altogether. Conditions for coexistence have mostly been studied by population and community ecology, while rates of invasion and fixation have mostly been studied by population genetics. In order to provide a global understanding of th…
We model a general, hierarchically organized tissue by a multi compartment approach, allowing any number of mutations within a cell. We derive closed solutions for the deterministic clonal dynamics and the reproductive capacity of single clones. Our results hold for the average dynamics in a hierarchical tissue characterized by an arbitrary combination of proliferation parameters.
We study the genetic behaviour of a population formed by haploid individuals which reproduce asexually. The genetic information for each individual is stored along a bit-string (or chromosome) with L bits, where 0-bits represent the wild-type allele and 1-bits correspond to harmful mutations. Each newborn inherits this chromosome from its parent with some few random mutations: on average a fixed number m of bits are flipped. Selection is implemented according to the number N of 1-bits counted along the individual's chromosome: the smaller N the higher the probability an individual has to survi…
We consider an asexual biological population of constant size $N$ evolving in discrete time under the influence of selection and mutation. Beneficial mutations appear at rate $U$ and their selective effects $s$ are drawn from a distribution $g(s)$. After introducing the required models and concepts of mathematical population genetics, we review different approaches to computing the speed of logarithmic fitness increase as a function of $N$, $U$ and $g(s)$. We present an exact solution of the infinite population size limit and provide an estimate of the population size beyond which it is valid.…
The prevalence of sexual reproduction ("sex") in eukaryotes is an enigma of evolutionary biology. Sex increases genetic variation only tells its long-term superiority in essence. The accumulation of harmful mutations causes an immediate and ubiquitous pressure for organisms. Contrary to the common sense, our theoretical model suggests that reproductive rate can influence initiatively the accumulation of harmful mutations. The interaction of reproductive rate and the integrated harm of mutations causes a critical reproductive rate R*. A population will become irreversibly extinct once the repro…
We study the adaptation dynamics of an initially maladapted asexual population with genotypes represented by binary sequences of length $L$. The population evolves in a maximally rugged fitness landscape with a large number of local optima. We find that whether the evolutionary trajectory is deterministic or stochastic depends on the effective mutational distance $d_{\mathrm{eff}}$ upto which the population can spread in genotype space. For $d_{\mathrm{eff}}=L$, the deterministic quasispecies theory operates while for $d_{\mathrm{eff}} < 1$, the evolution is completely stochastic. Between thes…
During chronic infection, HIV-1 engages in a rapid coevolutionary arms race with the host's adaptive immune system. While it is clear that HIV exerts strong selection on the adaptive immune system, the characteristics of the somatic evolution that shape the immune response are still unknown. Traditional population genetics methods fail to distinguish chronic immune response from healthy repertoire evolution. Here, we infer the evolutionary modes of B-cell repertoires and identify complex dynamics with a constant production of better B-cell receptor mutants that compete, maintaining large clona…
We reformulate the eigenvalue problem for the selection--mutation equilibrium distribution in the case of a haploid asexually reproduced population in the form of an equation for an unknown probability generating function of this distribution. The special form of this equation in the infinite sequence limit allows us to obtain analytically the steady state distributions for a number of particular cases of the fitness landscape. The general approach is illustrated by examples; theoretical findings are compared with numerical calculations.
This paper studies the mutation-selection balance in three simplified replication models. The first model considers a population of organisms replicating via the production of asexual spores. The second model considers a sexually replicating population that produces identical gametes. The third model considers a sexually replicating population that produces distinct sperm and egg gametes. All models assume diploid organisms whose genomes consist of two chromosomes, each of which is taken to be functional if equal to some master sequence, and defective otherwise. In the asexual population, the …
Which factors govern the evolution of mutation rates and emergence of species? Here, we address this question using a first principles model of life where population dynamics of asexual organisms is coupled to molecular properties and interactions of proteins encoded in their genomes. Simulating evolution of populations, we found that fitness increases in punctuated steps via epistatic events, leading to formation of stable and functionally interacting proteins. At low mutation rates, species - populations of organisms with identical genotypes - form, while at higher mutation rates, species ar…
This paper develops simplified mathematical models describing the mutation-selection balance for the asexual and sexual replication pathways in {\it Saccharomyces cerevisiae}. We assume diploid genomes consisting of two chromosomes, and we assume that each chromosome is functional if and only if its base sequence is identical to some master sequence. The growth and replication of the yeast cells is modeled as a first-order process, with first-order growth rate constants that are determined by whether a given genome consists of zero, one, or two functional chromosomes. In the asexual pathway, w…
Competition between independently arising beneficial mutations is enhanced in spatial populations due to the linear rather than exponential growth of clones. Recent theoretical studies have pointed out that the resulting fitness dynamics is analogous to a surface growth process, where new layers nucleate and spread stochastically, leading to the build up of scale-invariant roughness. This scenario differs qualitatively from the standard view of adaptation in that the speed of adaptation becomes independent of population size while the fitness variance does not. Here we exploit recent progress …
When mutation rates are low, natural selection remains effective, and increasing the mutation rate can give rise to an increase in adaptation rate. When mutation rates are high to begin with, however, increasing the mutation rate may have a detrimental effect because of the overwhelming presence of deleterious mutations. Indeed, if mutation rates are high enough: 1) adaptation rate can become negative despite the continued availability of adaptive and/or compensatory mutations, or 2) natural selection may be disabled because adaptive and/or compensatory mutations -- whether established or newl…
The evolution of microbial and viral organisms often generates clonal interference, a mode of competition between genetic clades within a population. In this paper, we show that interference strongly constrains the genetic and phenotypic complexity of evolving systems. Our analysis uses biophysically grounded evolutionary models for an organism's quantitative molecular phenotypes, such as fold stability and enzymatic activity of genes. We find a generic mode of asexual evolution called phenotypic interference with strong implications for systems biology: it couples the stability and function o…
How fast does a population evolve from one fitness peak to another? We study the dynamics of evolving, asexually reproducing populations in which a certain number of mutations jointly confer a fitness advantage. We consider the time until a population has evolved from one fitness peak to another one with a higher fitness. The order of mutations can either be fixed or random. If the order of mutations is fixed, then the population follows a metaphorical ridge, a single path. If the order of mutations is arbitrary, then there are many ways to evolve to the higher fitness state. We address the ti…
Because mutations are mostly deleterious, mutation rates should be reduced by natural selection. However, mutations also provide the raw material for adaptation. Therefore, evolutionary theory suggests that the mutation rate must balance between adaptability - the ability to adapt - and adaptedness - the ability to remain adapted. We model an asexual population crossing a fitness valley and analyze the rate of complex adaptation with and without stress-induced mutagenesis - the increase of mutation rates in response to stress or maladaptation. We show that stress-induced mutagenesis increases …
In unicellular organisms such as bacteria and in most viruses, mutations mainly occur during reproduction. Thus, genotypes with a high birth rate should have a higher mutation rate. However, standard models of asexual adaptation such as the 'replicator-mutator equation' often neglect this effect. In this study, we investigate the emergence of a positive dependence between the birth rate and the mutation rate in models of asexual adaptation and the consequences of this dependence. We show that it emerges naturally at the population scale, based on a large population limit of a stochastic timeco…
We consider an interacting particle Markov process for Darwinian evolution in an asexual population with non-constant population size, involving a linear birth rate, a density-dependent logistic death rate, and a probability $μ$ of mutation at each birth event. We introduce a renormalization parameter $K$ scaling the size of the population, which leads, when $K\to+\infty$, to a deterministic dynamics for the density of individuals holding a given trait. By combining in a non-standard way the limits of large population ($K\to+\infty$) and of small mutations ($μ\to 0$), we prove that a time scal…
We investigate the process of fixation of advantageous mutations in an asexual population. We assume that the effect of each beneficial mutation is exponentially distributed with mean value $ω_{med}=1/β$. The model also considers that the effect of each new deleterious mutation reduces the fitness of the organism independent on the previous number of mutations. We use the branching process formulation and also extensive simulations to study the model. The agreement between the analytical predictions and the simulational data is quite satisfactory. Surprisingly, we observe that the dependence o…
Following transmission, HIV-1 evolves into a diverse population, and next generation sequencing enables us to detect variants occurring at low frequencies. Studying viral evolution at the level of whole genomes was hitherto not possible because next generation sequencing delivers relatively short reads. We here provide a proof of principle that whole HIV-1 genomes can be reliably reconstructed from short reads, and use this to study the selection of immune escape mutations at the level of whole genome haplotypes. Using realistically simulated HIV-1 populations, we demonstrate that reconstructi…
We consider the dynamics of a non-recombining haploid population of finite size which accumulates deleterious mutations irreversibly. This ratchet like process occurs at a finite speed in the absence of epistasis, but it has been suggested that synergistic epistasis can halt the ratchet. Using a diffusion theory, we find explicit analytical expressions for the typical time between successive clicks of the ratchet for both non-epistatic and epistatic fitness functions. Our calculations show that the inter-click time is of a scaling form which in the absence of epistasis gives a speed that is de…
University of Toronto（多伦多大学）；Ontario Institute for Cancer Research（安大略癌症研究所）
High-throughput sequencing allows the detection and quantification of frequencies of somatic single nucleotide variants (SNV) in heterogeneous tumor cell populations. In some cases, the evolutionary history and population frequency of the subclonal lineages of tumor cells present in the sample can be reconstructed from these SNV frequency measurements. However, automated methods to do this reconstruction are not available and the conditions under which reconstruction is possible have not been described. We describe the conditions under which the evolutionary history can be uniquely reconstruct…
Muller's ratchet describes the irreversible accumulation of deleterious mutations in asexual populations. In well-mixed populations the speed of fitness decline is exponentially small in the population size, and any positive rate of beneficial mutations is sufficient to reverse the ratchet in large populations. The behavior is fundamentally different in populations with spatial structure, because the speed of the ratchet remains nonzero in the infinite size limit when the deleterious mutation rate exceeds a critical value. Based on the relation between the spatial ratchet and directed percolat…
Cancer results from a sequence of genetic and epigenetic changes which lead to a variety of abnormal phenotypes including increased proliferation and survival of somatic cells, and thus, to a selective advantage of pre-cancerous cells. The notion of cancer progression as an evolutionary process has been experiencing increasing interest in recent years. Many efforts have been made to better understand and predict the progression to cancer using mathematical models; these mostly consider the evolution of a well-mixed cell population, even though pre-cancerous cells often evolve in highly structu…
Cancer progression is an evolutionary process that is driven by mutation and selection in a population of tumor cells. We discuss mathematical models of cancer progression, starting from traditional multistage theory. Each stage is associated with the occurrence of genetic alterations and their fixation in the population. We describe the accumulation of mutations using conjunctive Bayesian networks, an exponential family of waiting time models in which the occurrence of mutations is constrained to a partial temporal order. Two opposing limit cases arise if mutations either follow a linear orde…
We consider an infinite asexual population with a mutator allele which can elevate mutation rates. With probability $f$, a transition from nonmutator to mutator state occurs but the reverse transition is forbidden. We find that at $f=0$, the population is in the state with minimum mutation rate and at $f=f_c$, a phase transition occurs between a mixed phase with both nonmutators and mutators and a pure mutator phase. We calculate the critical probability $f_c$ and the total mutator fraction $Q$ in the mixed phase exactly. Our predictions for $Q$ are in agreement with those seen in microbial po…
When beneficial mutations are relatively common, competition between multiple unfixed mutations can reduce the rate of fixation in well-mixed asexual populations. We introduce a one dimensional model with a steady accumulation of beneficial mutations. We find a transition between periodic selection and multiple-mutation regimes. In the multiple-mutation regime, the increase of fitness along the lattice bears a striking similarity to surface growth phenomena, with power law growth and saturation of the interface width. We also find significant differences compared to the well-mixed model. In ou…
